Donepezil interactions to avoid

Drug interactions | Food interactions | Other interactions | Avoiding interactions | When to see a doctor

Donepezil hydrochloride, known by the brand name Aricept, is approved by the U.S. Food and Drug Administration (FDA) to help manage Alzheimer’s Disease. It is also used off-label for other forms of dementia. Donepezil is available as a tablet, an orally disintegrating tablet, and a weekly patch. It is a central acetylcholinesterase inhibitor. Acetylcholinesterase is an enzyme responsible for the breakdown of acetylcholine. A deficiency of acetylcholine characterizes forms of dementia that donepezil manages, and donepezil appears to increase available concentrations of this molecule. However, donepezil use comes with a risk of side effects including cardiac effects, loss of appetite resulting in weight loss, and the development of muscle cramps. The patch may cause a local reaction at the application site, but this shouldn’t be mistaken for an allergic reaction to the medication. Donepezil interacts with anticholinergic agents, antipsychotic agents, medications that slow the heart rate, and other medications that impact cardiac conduction. It’s important to be aware of donepezil’s drug interactions as other drugs, supplements, and foods can affect its effectiveness or worsen side effects.

Donepezil drug interactions

Donepezil interacts with several classes of medications, including many that impact the central nervous system (CNS) and the heart. In some instances, combinations may increase side effects like the development of stomach ulcers. Below is a review of the more common and serious drug-drug interactions.

Anticholinergic and cholinergic drugs

Donepezil and acetylcholinesterase inhibitors may decrease the effect of anticholinergic agents, and likewise, anticholinergic agents may decrease the effect of acetylcholinesterase inhibitors. Anticholinergic drugs and acetylcholinesterase inhibitors combined work against each other—anticholinergics block the effects of acetylcholine, while acetylcholinesterase inhibitors prevent its breakdown. The overall result is a diminished therapeutic effect, which may worsen symptoms of Alzheimer’s Disease. Product labels acknowledge the opposing mechanisms and recommend avoidance of the combination whenever possible.

Examples of anticholinergic medications include:

• Elavil
• Atropine
• Cetirizine
• Diphenhydramine
• Loratadine
• Pamelor
• Quinidine
• Scopolamine

Acetylcholinesterase inhibitors, like donepezil, may impact the metabolism of cholinergic medications, which are also metabolized by cholinesterases. This will increase those cholinergic medication therapeutic levels, possibly resulting in enhanced cholinergic effects, including increased salivary and bronchial secretions and urinary bladder stimulation. 

Examples of cholinergic medications include:

• Methacholine
• Bethanechol
• Pilocarpine
• Rivastigmine

Antipsychotic medications

Donepezil may interact with certain antipsychotic agents, like aripiprazole, clozapine, haloperidol, lurasidone, olanzapine, quetiapine, and ziprasidone by enhancing the neurotoxic effects of these medications. The result is the development of extrapyramidal symptoms, including muscle rigidity, shuffling gait, and uncontrolled facial movements. The mechanism behind this interaction is due to the pharmacology of each medication—increased acetylcholine in the CNS coupled with dopamine receptor blockade. The combination should be avoided as some case reports have outlined an onset of severe extrapyramidal symptoms within days of initiating specific antipsychotics with donepezil. 

Neuromuscular blockers

Donepezil may enhance the neuromuscular-blocking effect of succinylcholine. Individuals requiring neuromuscular blockade and receiving donepezil should be monitored for prolonged effects of the blockade. The mechanism of this interaction is likely decreased metabolism of succinylcholine due to the inhibition of acetylcholinesterase brought on by donepezil. Fortunately, neuromuscular blockers are only employed in controlled medical settings where patients are closely monitored. 

Heart rate-lowering medications

Donepezil may slow down the heart rate. Thus, when combined with other medications, which also intentionally or unintentionally slow the heart rate, additive bradycardia may occur. Some classes of medications, such as beta blockers and certain calcium channel blockers, are taken for their heart rate-lowering effects. Other medications like lacosamide, which is an antiepileptic, have blocking effects on the heart’s atrioventricular (AV) node. This results in partial or complete disruption of impulse transmission from the atria to the ventricles, thus slowing the heart rate. It is important to be aware of symptoms of slowed heart rate, which manifest due to the lack of oxygen perfusing major organs and systems, including chest pain, confusion, dizziness, fatigue, and syncope. The onset of any of these symptoms warrants emergency medical services. 

Medications implicated to cause bradycardia include:

• Adenosine
• Amiodarone
• Atenolol
• Bisoprolol
• Carvedilol
• Clonidine
• Digoxin
• Diltiazem
• Labetalol
• Metoprolol
• Nadolol
• Propranolol 
• Rivastigmine
• Sotalol
• Verapamil

QTc-prolonging medications

Donepezil may enhance the QTc-prolonging effect of other medications with just a single dose, which can result in life-threatening heart rhythm patterns like torsades de pointes. The QT interval is the part of an electrocardiogram (EKG) report that represents the time it takes the heart to contract and recover. Long QT syndromes can be inherited and are the result of an issue with the heart’s electrical conduction such that it takes longer than normal to recharge between heartbeats, which is due to an issue with ion channels or the flow of ions (sodium, calcium, potassium, and chloride) in and out of heart muscle cells to produce electrical activity. Medications can cause acquired long QT syndrome. When the QT interval is prolonged, the risk for irregular heartbeats like ventricular tachycardias is increased, which can result in cardiac arrest and sudden death due to the heart’s inability to pump blood throughout the body effectively. 

The classes of drugs that can independently prolong the QTc interval are listed below. 

Antiarrhythmic medications:

• Class IA antiarrhythmics
  • Disopyramide
  • Procainamide
  • Quinidine
• Class III antiarrhythmics
  • Amiodarone
  • Dofetilide
  • Dronedarone
  • Ibutilide
  • Sotalol
• Miscellaneous antiarrhythmics
  • Digoxin

Fluoroquinolone antibiotics:

• Ciprofloxacin
• Delafloxacin
• Levofloxacin
• Moxifloxacin

Macrolide antibiotics:

• Azithromycin
• Clarithromycin
• Erythromycin

Azole antifungals:

• Ketoconazole
• Isavuconazole
• Posaconazole
• Itraconazole
• Voriconazole

Antipsychotics:

• Pimozide
• Ziprasidone

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs are medications that are used very often in the management of acute pain. Some approved indications include osteoarthritis, rheumatoid arthritis, and juvenile rheumatoid arthritis. NSAIDs are often consumed outside of these indications for their ability to improve symptoms such as pain, stiffness, swelling, and tenderness of the joints. Many NSAIDs are available over-the-counter (OTC) as non-prescription medications, so they are readily accessible to individuals. OTC medications can go under-recognized as contributing to significant drug interactions and adverse effects. One study found an increased risk of peptic ulcers with the coadministration of NSAIDs and cholinesterase inhibitor donepezil, beyond the risk with NSAID use alone.  

NSAIDs include the following medications:

• Celecoxib
• Diclofenac
• Etodolac
• Ibuprofen
• Indomethacin
• Ketorolac
• Meloxicam
• Naproxen

Anticonvulsants

Some anticonvulsants may interact with donepezil. This becomes of greatest concern in older adult patients with an Alzheimer’s diagnosis and a concurrent epilepsy diagnosis. Anticonvulsants with enzyme-inducing properties like carbamazepine, phenytoin, and phenobarbital may decrease blood levels of donepezil. Individuals receiving one of these anticonvulsants may be better managed with alternative agents than donepezil and vice versa. If the combination cannot be avoided, individuals and their caregivers should be educated on the risk of increased symptoms of Alzheimer’s disease while receiving the combination. 

Corticosteroids

Concomitantly taking corticosteroids with donepezil may enhance their adverse effects, including increased risk of muscle weakness. Patients taking these two types of medications together should be monitored for an exacerbation of muscle weakness, with a dose reduction or tapering donepezil considered in the setting of a need for high-dose steroids. Starting high-dose steroids for an acute reason in a patient on an acetylcholinesterase inhibitor should be done in a hospital setting so that close monitoring can be provided. The mechanism of this action appears to be an additive effect since both classes can cause dose-dependent weakness. The onset of the additive effect could take 1 to 2 weeks and may be severe enough to require emergency medical interventions like ventilatory support. Since donepezil is a central nervous system selective acetylcholinesterase inhibitor, the risk of the additive effect may not be reduced, but it remains a possibility. The manufacturer of dexamethasone products recommends withdrawal of anticholinergic agents at least 24 hours before initiation of steroid therapy in its packaging. Any level of steroid consumption while taking donepezil should be done under the supervision of a healthcare provider, and individuals should seek immediate medical attention with any onset of muscle weakness. 

Corticosteroids include the following medications:

• Betamethasone
• Dexamethasone
• Florinef (fludrocortisone)
• Cortef (hydrocortisone)
• Medrol (methylprednisolone)
• Orapred (prednisolone)
• Prednisone

Donepezil food interactions

Donepezil and grapefruit 

Grapefruit interacts with many prescription drugs by inhibiting a particular hepatic enzyme linked to the metabolism of many medications. Donepezil is a weak substrate of this enzyme, known as CYP3A4. Therefore, acute changes in the consumption of grapefruit juice may increase the blood concentrations of donepezil. It is best to consistently consume the same moderate amount of grapefruit juice when on donepezil or avoid it entirely. 

Other donepezil interactions

Donepezil and alcohol 

While there is no direct interaction between donepezil and alcohol, it is best to avoid alcohol when taking this medication. Alcohol combined with donepezil may increase the side effects experienced, but more importantly, alcohol may exacerbate the conditions for which donepezil is prescribed. 

Donepezil and caffeine

Caffeine interacts with many prescription drugs. One animal study has demonstrated that up to moderate caffeine consumption levels may improve donepezil’s antioxidant properties. However, moderate caffeine consumption may reduce donepezil’s anticholinesterase effects compared to low consumption. In severe Alzheimer’s disease, this could exacerbate symptoms. 

Donepezil and Huperzia

Huperzia is a type of moss that grows in China and is used in traditional Chinese medicine practices to manage age-related cognitive decline and Alzheimer’s disease. Huperzia moss may be ingested as a tea. It is reported to work by preventing the breakdown of acetylcholine, which is a similar mechanism to donepezil. While significant data on this interaction is lacking, it is best to avoid the combination given the similar mechanisms (presumed or known). 

Donepezil and St John’s wort

St. John’s wort is a supplement used for effects on depression but can cause interactions with many medications. St. John’s wort does interact with donepezil, resulting in decreased levels of donepezil. This could affect the symptoms for which donepezil is consumed, and concomitant use should be avoided. 

Donepezil and Lung Disease

Drugs used to control dementia and symptoms of Alzheimer’s Disease in individuals who also have lung diseases like asthma and chronic obstructive pulmonary disease (COPD) may experience an increase in the risk of exacerbation, especially in the first 90 days of use. 

How to minimize donepezil interactions

Always carry a complete list of medications, including supplements, on your person. Whenever you ask your doctor for medical advice, share this list with them. It helps them carefully check and assess your medications to reduce the chances of any problems caused by drug interactions. If interactions occur, even if the signs or symptoms are mild, it is best to review them with your healthcare professional. 

When to talk to a healthcare provider about donepezil interactions

This article is not a complete list of donepezil interactions. Be mindful of the risk of donepezil when used in combination with prescription and over-the-counter medications. Communicate with a healthcare professional anytime you use donepezil so that a comprehensive review of interactions can occur, including interference with known medical conditions, to ensure proper management and monitoring.